The incidence of esophageal adenocarcinoma is increasing more rapidly than any other cancer in the United States. The reasons for this rapid increase are unknown, and large, population-based studies of this disease are only now beginning. Approximately 2 million persons in the U.S. have Barrett's esophagus, a condition in which the squamous epithelium of the lower esophagus has been replaced by a metaplastic columnar epithelium as a result of chronic gastroesophageal reflex disease (GERD). They are at much higher risk (perhaps 30-fold) of developing this cancer. Cancer surveillance for these patients is invasive and expensive, and existing therapies, while useful in controlling reflux symptoms, apparently do not reduce the rate of neoplastic progression. The overall goal of our research is to determine methods that can identify the subset of persons with Barrett's esophagus who are most likely to progress to esophageal adenocarcinoma. The study's first aim is to investigate intermediate markers in esophageal biopsies (cell cycles abnormalities and somatic genetic abnormalities) as predictors of neoplastic progression in persons with Barrett's esophagus. In the clinical setting, this would be useful in identifying those persons needing the most frequent surveillance. In the research setting, valid intermediate endpoints would facilitate both prevention trials and etiologic studies. The second aim is to identify environmental risk factors for progression that are amenable to intervention (e.g., dietary fat intake, obesity, medication use, smoking, and alcohol) and to measure their association with intermediate events of neoplastic progression identified in the first specific aim. The third aim is to devise and test a practical endoscopic biopsy protocol for use in community practice, population-based epidemiologic studies, and prevention trials. Eligible subjects (N=325) for this cohort study will be selected from a registry of patients (males and females of all races) who have undergone endoscopy and biopsy as part of the University of Washington's Barrett's Esophagus Project. Data will be collected via in- person interviews, endoscopies with multiple biopsies, anthropometry, dietary assessments, and serum measures of antioxidants. DNA content and multiparameter flow cytometry, cell sorting, PCR, and DNA sequencing will be used to assess cell cycle abnormalities, aneuploidy, 17p allelic losses, and p53 mutations. Statistical analyses, which vary by specific aim, will include logistic regression (adjusting for length of follow-up) and construction of ROC curves.